Brain grafting has emerged as a novel therapy for patients suffering from Parkinson's disease who are refractory to medical therapy. Behavioral recovery following caudate cavitation in Parkinsonian monkeys has focused our attention on potentially beneficial host responses to grafting. Following injury the CNS produces neurotrophic factors which promote neurite outgrowth and glial proliferation. We have explored the therapeutic potential of growth factors in preventing or reversing biochemical and behavioral parameters in rodent models of Parkinson's disease. To further investigate the physiology of nerve growth factors we have lesioned the dopamine system in mice with MPTP and measured the transcription of brain-derived neurotrophic factor (DBNF) and neurotrophin-3 using Northern blotting. To deliver growth factors to gray matter we are developing methods for convection-enhanced direct infusion and ex vivo gene therapy. We used convection to enhance the distribution of large molecules injected into the striatum in rats, measured using immunohistochemistry and quantitative autoradiography. We are beginning to explore the viability and biology of fetal human glial cells after transplant in mice, rats, and monkeys as an alternative paradigm to continuously deliver proteins to the degenerating dopamine system. Recent electrophysiologic and anatomic studies have shown hyperactivity of neurons in the subthalamic and globus palladium interna nuclei produce the symptoms of Parkinson's disease. Accordingly, we are exploring the use of excitatory amino acids to destroy the globus pallidus interna in monkeys as a novel therapy.